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Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
Division of Nuclear Medicine, Department of Radiology, The Johns Hopkins Medical School, Baltimore, Maryland
Correspondence: For correspondence or reprints: Ursula Scheffel, Sc D Medicine Research, 220 Ross Research, The Johns Hopkins Medical School, Rutland Avenue, Baltimore, MD 21205-2196.
ABSTRACT
Visualization of central nicotinic acetylcholine receptors (nAChRs) with modern PET or SPECT imaging techniques has been hampered by the lack of a radioligand with suitable in vivo binding characteristics (i.e., high target-to-nontarget ratios and kinetics appropriate for the half-life of the tracer and imaging modality used). This paper describes in vivo binding, kinetics and pharmacology of a highly potent 18F-labeled analog of epibatidine,(±)-exo-2-(2-[18]fluoro-5-pyridyl)-7-azabicyclo [2.2.1] heptane ([18]FPH), in the mouse brain with the view towards application of this tracer for PET imaging of nAChR in human brain. Methods: Fluorine-18-FPH was administered intravenously to mice, and time-activity curves were determined for several regions in the brain and other organs. Saturation and pharmacology of [18]FPH binding was demonstrated in vivo by preinjecting unlabeled FPH or other drugs with known pharmacological action before [18]FPH was injected. The effect of the drugs on [18]FPH accumulation was evaluated. Results:[18]FPHwas rapidly incorporated into the mouse brain; peak activity (2.4% of the injected dose)was measured at 5 min after intravenous administration, followed by washout to 1.1% injected dose (ID) at 60 min. Highest concentrations of 18F occurred at 15 min in areas known to contain high densities of nAChR {e.g., thalamus [9.7% of injected dose per gram tissue (ID/g)] and superior colliculus (8.3%ID/g)}. Accumulation of the 18Ftracer in hippocampus, striatum, hypothalamus and cortical areas was intermediate (5.0,5.6,4.2 and 5.6%ID/g, respectively) and low in the cerebellum (2.8%ID/g). The distribution of [18]FPHin the mouse brain matched that of other in vivo nAChR probes such as 3H-labeled epibatidine or norchloroepibatidine, [3](–)-nicotine and pHjcytisine and that of nAChR densities determined in postmortem autoradiographic studies in rodents. Preinjection of blocking doses of unlabeled epibatidine, (–)-nicotine, lobeline and cytisine significantly inhibited [18]FPH binding in thalamus and superior colliculus, but not in cerebellum, whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR (e.g.,mecamylamine, scopolamine, N-methylspiperone and ketanserin)had no effect on [18]FPH accumulation in any of the brain regions examined. Conclusion: Fluorine-18-FPH labels nAChR in vivo in the mouse brain. Because of its high uptake into the brain and high ratios of specific-to-nonspecific binding, this radioligand appears to be ideally suited for PET imaging of nAChR in the mammalian brain.
Key Words: nicotinic acetylcholine receptor • brain imaging • PET
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